Molecular insights on TNKS1/TNKS2 and inhibitor-IWR1 interactions.

Tankyrases (TNKS) belong to the poly(ADP-ribose)polymerase (PARP) protein super family and play a vital role in the Wnt/β-catenin signaling pathway. TNKS is a potential target for therapeutic intervention against various cancers, heritable diseases (e.g. cherubism) and implications in the replication of herpes simplex virus (HSV). The recent discovery of the structure of TNKS with an IWR1 inhibitor has provided insight into the binding modes which are specific for the TNKS protein which will aid in the development of drugs that are specific for the TNKS protein. The current study investigates molecular interactions between the induced pocket of TNKS1 and TNKS2 with an IWR1 compound using computational approaches. Molecular docking analysis of IWR1 at the induced pocket of TNKS1 and TNKS2 was performed. The resulting protein-ligand complexes were simulated for a timescale of 100 ns. Results revealed the stable binding of IWR1 at the induced pocket of TNKS1 and TNKS2 proteins. Apart from active site amino acids, π-π stack paring interactions were also crucial for the protein-ligand binding and stability of the complex. Further, energy-optimized pharmacophore mapping was performed and the resulting pharmacophore model contained a four (TNKS1-IWR1) and five (TNKS2-IWR1) featured sites. Based on the pharmacophore models, the best inhibitors were screened from the ZINC natural product compound database and these could be used as potential drugs against TNKS1 and TNKS2.